How do translocations such as the Philadelphia chromosome contribute to cancer?

A chromosomal translocation occurs when a segment of genetic material from one chromosome breaks off and reattaches to a different chromosome. This transfer of genetic information can lead to a variety of genetic disorders and health problems, including cancer. In some cases, the translocation may cause a gene to become overactive, or it could disrupt the normal function of a gene and lead to uncontrolled cell growth.

The Philadelphia chromosome is a specific chromosomal translocation between chromosome 9 and chromosome 22, commonly designated as t(9;22)(q34;q11). This chromosomal abnormality is named after the city where it was first discovered, and it is associated with a particular type of blood cancer called chronic myelogenous leukemia (CML).

The Philadelphia chromosome arises from a reciprocal translocation between chromosomes 9 and 22. A piece of chromosome 9 containing the Abl1 gene is translocated onto chromosome 22, while a piece of chromosome 22 containing the BCR gene is translocated onto chromosome 9. As a result, the ABL1 gene from chromosome 9 is fused to the BCR gene located on chromosome 22, thus creating a new fusion gene known as BCR-ABL1.

The fusion of the BCR and ABL1 genes produces an abnormal protein called BCR-ABL1, which has a continuous tyrosine kinase activity. This consistent activity disrupts the cell signaling pathways and promotes uncontrolled cell growth and proliferation. The accumulation of these abnormal cells in the bone marrow and blood results in the development of chronic myelogenous leukemia (CML). The presence of the Philadelphia chromosome is detected in approximately 95% of people with CML, making it a diagnostic hallmark and a therapeutic target for this type of cancer.

Since the uncontrolled activity of the BCR-ABL1 tyrosine kinase drives the development of CML, targeting this abnormal protein is a critical therapeutic approach. Imatinib, also known as Gleevec, is a drug that specifically inhibits the activity of the BCR-ABL1 protein, leading to decreased cell growth and increased cell death in Philadelphia chromosome-positive CML. This targeted therapy has revolutionized the treatment of CML and has significantly improved the prognosis for individuals with this disease. In conclusion, translocations such as the Philadelphia chromosome contribute to cancer by creating fusion genes that drive uncontrolled cell growth. In the case of the Philadelphia chromosome, the BCR-ABL1 fusion gene promotes the development of chronic myelogenous leukemia.